Inhaled medium acting .beta.-agonists are the most commonly prescribed asthma treatments in the world. .beta.-agonists produce their effects by stimulating the .beta..sub.2 -adrenergic receptors on cells and thereby activating intracellular pathways that produce increased levels of cyclic adenosine monophosphate (cAMP). The increased intracellular cAMP levels in turn produce macroscopic effects in the cells, relaxing the smooth muscles of the bronchial airways, increasing ciliary beat frequency, and reducing mucous viscosity. The effectiveness of .beta.-agonists at dilating bronchial airways has led to their widespread administration both as a treatment for acute asthmatic episodes and as a long-term asthma management therapy.
Concerns about the safety of .beta.-agonist therapy have arisen periodically over the years (reviewed in, for example, Taylor et al., Med. Clin. N. America 80:719, 1996; Giunti et al., Eur. Respir. J. 8:673, 1995; Barrett et al., Am. J. Respir. Crit. Care Med. 151:574, 1995; Devoy et al., Chest 107:1116, 1995; McFadden, Ann. Allergy Asthma Immunol. 75:173, 1995; Crane et al., Thorax 50:S5, 1995; McFadden, J. Allergy Clin. Immunol. 95:41, 1995). Reports of possible associations between .beta.-agonist administration and increased morbidity, particularly for chronic .beta.-agonist administration protocols, have spurred much debate over the safety of .beta.-agonist therapy. There is a need to resolve this debate and to identify risks of deleterious or salutory effects associated with administration of .beta.-agonists to asthmatics.